Production of aminoacid precursors

ABSTRACT

The invention relates to the substitution of one or two hydrogen atoms on the Alpha -carbon atom of an Alpha -isocyanocarboxylic acid derivative by means of an alkylating agent and using a metallizing agent.

United States Patent [191 Schoellkopf et a1.

[ June 18, 1974 1 PRODUCTION OF AMINOACID PRECURSORS [75] Inventors:Ulrich Schoellkopf, Bovenden; Fritz Gerhart, Goettingen; Dieter Hoppe,Goettingen; Reinhard Jentsch, Goettingen, all of Germany [73] Assignee:Badische Anilin- & Soda-Fabrik Aktiengesellschaft, Ludwigshafen/Rhein.Germany [22] Filed: Dec. 22, 1971 [21] Appl. No.: 211,112

[30] Foreign Application Priority Data Dec. 23, 1970 Germany 2063502 [56] References Cited UNITED STATES PATENTS 3,712,911 1/1973 Schoellkopfet a1. 260/465.4 X

OTHER PUBLICATIONS Migrdichian, Organic Synthesis, Vol. 1, 1957 pp.

733-739, Reinhold Pub. Co. J. Org. Chem, Vol. 28, No. 6, June 1963Kay-Fries Chem. Add, p. 1733.

Primary Examiner-Joseph P. Brust Attorney, Agent, or FirmJohnston, Keil,Thompson & Shuttleff [57] ABSTRACT The invention relates to thesubstitution of one or two hydrogen atoms on the a-carbon atom of ana-isocyanocarboxylic acid derivative by means of an alkylating agent andusing a metallizing agent.

15 Claims, N0 Drawings PRODUCTION OF AMINOACID PRECURSORS The inventionrelates to the production of aminoacid precursors by alkylation ofa-metallized esters of isocyanocarboxylic acids. They can be convertedin a simple way into aminoacids.

Among known methods for the synthesis of aminoacids the presentinvention is comparable in scope of its application to the method usingN-acylamidomalonic esters. This method includes a decarboxylation stepwhich in the case of sensitive substances may result in a substantialdecrease in yield (Houben-Weyl, 4th edition, volume XI/2, page 308).

We have now found that isocyanocarboxylic esters are obtained asprecursors of aminoacids by reacting an a-metallized isocyanocarboxylicester of the formula:

where R denotes hydrogen or an organic radical attached by way of acarbon atom; R denotes the radical of an alkyl derivative suitable foresterification and M denotes the radical of lithium, sodium, potassium,

magnesium, calcium or thallium with an alkylating agent to form acompound of the formula:

in which R denotes unsubstituted or substituted alkyl or when R denoteshydrogen, after its replacement by M, to form a compound of the formula:

in which R and R are like R or R and R together denote a chain of fromtwo to six members.

When R and R have the meanings given for R, they may be identical ordifferent.

Alkylating agents are compounds with which the metal radical in acompound of the formula (I) can be replaced by an alkyl or a substitutedalkyl radical. Alkylating agents include in particular alkyl halides,alkyl sulfates, alkyl esters of aromatic sulfonic acids and sultones,for example alkyl bromides and iodides, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl bromides and iodides, allyl bromide,bromohexane, dimethyl sulfate, diethyl sulfate, methyl or ethyltoluenesulfonate and the corresponding phosphoric esters. The 6 alkylradical may in turn bear substituents such as carboxyl, alkenyl orphenyl radicals and therefore be for example chloroacetic acid, estersof chloroacetic acid and benzyl halides. The alkyl radicals may also becy- 65 cloalkyl radicals. Epoxides, for example ethylene oxide, are alsosuitable alkylating agents for the purposes of the present invention.

Both halogen atoms in a alkyl dihalide for example both bromine atoms inl,4-dibromobutane, may be replaced by the isocyanocarboxylic esterradical. R in fonnula (ll) then bears the said radical twice:

Examples of other dihalogen compounds are: 1,4-dibromobutene,l-chloro-2-bromoethane, 2,2- dichlorodiethyl ether, 2,2-dichlorodiethylthioether or l,2-dibromoethane. The alkylating agent may therefore berepresented for example by the formula R X (X denoting the radical of anacid anion), RX (X denoting a halogen atom) or R X (X denoting a sultoneor oxa bridge).

The isocyanocarboxylic esters of formula (I) to be used as startingcompounds for this process may be obtained in known manner according tothe directions in German Laid-open Print No. 1,812,099.

In these starting compounds R may denote for example alkyl such asmethyl, ethyl, propyl 0r butyl; aryl such as phenyl; or cycloalkyl suchas cyclohexyl. The alkyl radicals may in turn bear substituents, forexample alkoxy or alkylthio radicals. An example of such a radical R isthe methylthioethyl radical. R may also denote a heterocyclic radical asfor example indolyl, imidazolyl, furyl, pyridyl or thienyl. R may denotefor example methyl, ethyl, propyl, butyl, t-butyl or benzyl. Since theradical R does not take part in the reaction according to this inventionthere are no special criteria in its choice. It may be left to theexpert to select suitable starting compounds (I) with the many possibleradicals R and this will not offer any difficulty.

Examples of individual compounds of the formula (I) are metallized ethylisocyanoacetate, t-butyl a-isocyanoacetate, ethyl a-isocyanopropionate,ethyl a-isocyano-a-(2-bromoethyl)-acetate, ethyl a-isocyanobutyrate,ethyl a-isocyanovalerate, ethyl a-isocyanocaproate, ethyla-isocyanoisobutyrate, ethyl a-isocyanovalerate, ethyla-isocyano-B-methylvalerate, ethyl a-isocyanophenylacetate (andderivatives thereof substituted in the nucleus), ethyla-isocyano-B-phenyl propionate, ethyl a-isocyano-B-indolylpropionate,ethyl a-isocyano-B-imidazolyl propionate, ethyl a-isocyano-Barylthiopropionates, ethyl a-isocyano-y-methylthiobutyrate, ethyla-isocyano-B-alkoxypropionate, ethyl a-isocyano-B-alkoxybutyrate,diethyl a-isocyanosuccinate, diethyl a-isocyano-glutyrate, and ethyla-isocyano-y-bromobutyrate.

Agents supplying M are particularly basic reagents of the type MX whereM denotes equivalent of one of the above-mentioned metals and X denotesan aliphatic or aromatic hydrocarbon radical, the radical of an alcohol,the radical of an acetylenic compound or OH. Metallizing agentsaccordingly include organometallic compounds, alkoxides, acetylides,hydroxides and Grignard compounds. Metallization can also be achievedwith metal hydrides or with metal amides and in some cases it ispossible to react the isocyanides direct with a metal to form metallizedisocyanides.

Examples of individual metallizing agents are butyl lithium, phenyllithium, phenyl sodium, sodium methylate, sodium ethylate, potassiumt-butylate, lithium tbutylate, potassium amide, sodium acetylide, phenylmagnesium bromide, magnesium hydroxide, sodium hydride, sodamide andsodium metal.

It is particularly advantageous in the process of the present inventionfor the a-metallized isocyanates (l) to be alkylated without isolation,after or during their formation by metallization by a conventionalmethod of the compound (Vl) (i.e., by bringing this compound togetherwith an agent supplying M). Compounds (Vl) may therefore be describedalso as a-metallizable compounds.

Organic liquids which are conventionally used for alkylation reactionsand which for improvement of the yield may be anhydrous are suitable asthe reaction medium. Examples are ethers such as diethyl ether,tetrahydrofuran and dioxane; dipolar aprotic solvents such asdimethylformamide, dimethylsulfoxide or acetonitrile or mixtures of twoor more of such liquids. Excess starting compound (l) or excessalkylating agent which is liquid at the reaction temperature may also beused as the reaction medium.

The reaction temperature for the alkylation depends on the reactivity ofthe starting compound and of the alkylating agent. The reactiontemperature generally is within the range from about 40 and about 70C.Temperatures down to 8 C and temperatures above 70C may also be useful.

in many cases it is advisable to bring the reactants together instoichiometric proportions, for example when disturbances ordifficulties in processing by excess starting compound or excessalkylating agent are to be avoided. Alkylation proceeds even withoutusing an additional base because the anionic radical of the alkylatingagent split off is bound by the metal radical. When a starting compoundis present in which R is hydrogen or a metal radical, the stoichiometricratio may be provided for by forming a compound of the formula (ll) orthe formula (lll) and in this way even different substituents R and Rmay be introduced.

When one component is used in excess which has a boiling point atatmospheric or subatmospheric pressure which lies in the temperaturerange of the reaction, the other can be dripped or run into the excessreactant and the excess evaporated ofi'.

The invention produces aminoacid precursors which can be converted intoaminoacids by hydrolysis. The hydrolysis in diiute acid first results ina N-formyl derivative (NCHO instead of NC) and if desired an aminederivative. Hydrolysis in alcoholic caustic alkali solution yields theN-formyl derivative with hydrolysis of the ester group. The methylaminederivative can be prepared from the compounds (ii) and (Ill) bycatalytic hydrogenation. When an alkyiating agent is used having aradical R which bears the radical of an acid anion which is capable ofreaction twice (R X the formation of the compounds of the formula (IV)and compounds of the formula (V) can be directed at will by means of themolar ratio of compound (I) (with R denoting hydrogen) and R X Thegreater the molar excess of compound (I) over the aikylating agent R Xthe greater is the tendency for the formation of compounds having theformula (IV). When the reaction mixture is very concentrated and themolar ratio of (l) to R X is chosen at 1: l or lzmore than l, compoundsof formula (V) are formed preferentially. When compounds (IV) and (V)are formed at the same time neither class of compound offers anydifficulty in isolation because of the difference physical behavior. Thereaction of the compounds of formula (I) (with R denoting hydrogen) withalkylating agents R X to form compounds of the formula (Vll):

also offers no difficulty because for this purpose about 1 mole ofmetallizing agent, 1 mole of (l) and 1 mole of R X can be used. Theproduction of oligomers and polymers of isocyanocarboxylic esters isthen possible by further metallization.

As compared with prior art methods for the production of aminoacids theprocess of this invention has a number of advantages: the startingcompounds are often more easily accessible, a very great variety ofsubstituents R and/or Rhu 5 may be introduced and the a-carbon atom mayalso bear two substituents. the conversion of the precursors into theaminoacids does not require the step of decarboxylation which isinconvenient for many sensitive substituents.

The following Examples illustrate the invention.

EXAMPLE I t-butyl a-isocyanopropionate:

40 ml of t-butyl isocyanoacetate in 10 ml of tetrahydrofuran is drippedwith stirring into 42 millimoles of potassium t-butanolate in 50 ml oftetrahydrofuran. The whole is allowed to heat up to 30 to 40C and 40millimoles of methyl iodide is dripped in. The whole is stirred untilthere is a neutral reaction, filtered, the solvent removed in vacuo. 200ml of ether and 50 ml of ice-water is added and the whole is worked upas usual. 60 percent of the t-butyl ester of a-isocyanopropionic acidhaving a boiling point of 73 to 75C at 10 mm is recovered from the etherphase.

EXAMPLE 2 a-isocyanopentene-4-acid t-butyl ester:

The procedure described in Example i is followed but allyl bromide isused. percent of the t-butyi ester 5 of a-isocyanopentene-4-acid isobtained having a boiling point of 105 to 110C at 10 mm.

EXAMPLE 3 t-butyl a-isocyano-B-methylbutyrate:

The procedure described in Example 2 is followed but with isopropylbromide. The t-butyl ester of a-isocyano-B-methylbutyric acid can beclearly detected in the crude product.

EXAMPLE 4 Ethyl a-isocyano-B-phenylisobutyrate:

40 millimoles of ethyl a-isocyanopropionate and then 42 millimoles ofbenzyl chloride are dripped while stirring, both at 60C, into 40millimoles of potassium tbutanolate in 25 ml of dry tetrahydrofuran. Thewhole is allowed to warm up to room temperature and is stirred untilthere is a neutral reaction. The solvent is removed in vacuo. Theresidue is shaken with 50 ml of ether and 25 ml of ice-water. The phasesare separated and worked up as usual. 6.7 g (79 percent) of ethyla-isocyano-B-phenylisobutyrate is obtained having a boiling point of 100to 105C at 0.05 mm.

For conversion into N-formyl-amethylphenylalanine. l millimoles isboiled under reflux in a solution of l millimole of potassium hydroxidein 20 ml of 90 percent ethanol for 30 minutes. The solvent is removed invacuo. The residue is dissolved in 50 ml of water and acidified to pH 2to 3 with 36 percent hydrochloric acid. The precipitated aminoacid iscrystallized, filtered off and recrystallized from a mixture of ethanoland water. 85 percent of N-formyl-amethylphenylalanine is obtained whichis identical with the authentic preparation.

EXAMPLE 5 Ethyl a-isocyano-a-methylcaproate:

The procedure described in Example 4 is followed but with n-butyliodide. The whole is stirred for min utes, worked up as described inExample 4 and 59 percent of ethyl a-isocyano-a-methylcaproate isobtained having a boiling point of 68 to 69C at 1.5 mm. Bysaponification as described in Example 4, 87 percent ofa-formylamino-a-methylcaproic acid is obtained.

EXAMPLE 6 Ethyl a-isocyano-a-methylcaprylate:

The procedure described in Example 4 is followed but withl-bromo-hexane. The whole is stirred for another 30 minutes and workedup as described in Example 4. 62 percent of ethyla-isocyano-ozmethylcaprylate is obtained having a boiling point of 82 to85C at 0.8 mm. Upon saponification as described in Example 4, 80 percentof a-formylamino-amethylcaprylic acid is obtained having a melting pointof 145C (Recrystallized from ethanolzwater 1:1).

EXAMPLE 7 Ethyl a-isocyanoa-butylcaproate:

millimoles of ethyl isocyanoacetate in 10 ml of tetrahydrofuran isdripped with stirring at 60C into 40 millimoles of potassiumt-butanolate in ml of tetrahydrofuran and then 42 millimoles of butyliodide is dripped in at -60C to -50C. The cooling bath is removed andthe whole is stirred at room temperature until at least 95 percent ofthe alkali used has been used up. The solvent is removed in vacuo. Theresidue is shaken with 50 ml of ether and 25 ml of ice-water. The phasesare separated and worked up as usual. 2.2 g (50 percent) of ethyla-isocyano-a-butylcaproate is obtained with a boiling point of to 82C at0.1 mm.

EXAMPLE 8 Ethyl a-isocyano-B, B-diphenylisobutyrate:

The procedure described in Example 7 is followed but with benzylbromide. The whole is stirred for ten minutes at room temperature andworked up as described in Example 7. 3.7 g (64 percent) of ethyla-isocyano-B,,Bdiphenylisobutyrate is obtained having a boiling point of150 to 153C at 0.05 mm.

EXAMPLE 9 A suspension of 40 millimoles of the ethyl ester of potassiumisocyanoacetic acid (prepared from ethyl isocyanoacetate and potassiumt-butanolate at 60C) in 40 ml of tetrahydrofuran is dripped at 20C whilestirring into a solution of 50 millimoles of benzyl bromide intetrahydrofuran. Conventional working up gives a mixture of ethyllisocyano-2-phenylpropionate and ethyl a-isocyano-B,B-diphenylisobutyrate.

EXAMPLE l0 Ethyl 0z-isocyanocyclopropanoate:

4O millimoles of sodium hydride (suspended in 30 ml of ether) is drippedat 20 to 25C with vigorous stirring into 40 millimoles of ethylisocyanoacetate and 40 millimoles of 1,2-dibromoethane in a mixture of40 ml of dry dimethylsulfoxide and 100 ml of dry ether (under nitrogen).The whole is further stirred without cooling until evolution of gas hasceased. The whole is then boiled for thirty minutes. The reactionmixture is poured into 100 ml of ice-water, the organic phase isseparated, extracted twice, each time with 50 ml of ether and theorganic phase is washed twice with 30 ml of water. The product is driedover sodium sulfate, the solvent is distilled off over a 25 cm columnand distilled in vacuo. 3.2 g (58 percent) of ethyla-isocyanocyclopropanoate is obtained having a boiling point of 91 to Cat 20 mm.

EXAMPLE 1 l Diethyl a-isocyano-a-methylsuccinate:

0.05 mole of ethyl isocyanopropionate is dripped at -5C while stirringinto a suspension of 0.05 mole of potassium t-butanolate in 50 mltetrahydrofuran. The whole is cooled to 70C and 0.05 mole of ethylchloroacetate is dripped in. This mixture is added from a droppingfunnel cooled with methanol and solid carbon dioxide in 50 ml oftetrahydrofuran preheated to 50C while stirring. The whole is heated forabout 30 minutes, the solvent is distilled off in vacuo, the residue isshaken with 20 ml of ice-water and 20 ml of ether and the ethereal phaseis worked up as usual. 31 percent of diethyla-isocyano-a-methylsuccinate is obtained; it has a boiling point of 72to 74C at 0.1 mm.

EXAMPLE l2 t-butyl a-isocyanocyclopentanoate:

0.05 mole of ethyl isocyanoacetate is dripped at 5 "C while stirringinto 0.1 mole of potassium t-butanolate in 50 ml of dry tetrahydrofuran.The whole is cooled to 70C and 0.05 mole of 1,4-dibromobutane is drippedin. This mixture is then added from a dropping funnel (cooled with amixture of methanol and solid carbon dioxide) to 50 ml oftetrahydrofuran (which has been preheated to 50C) while stirring. Thewhole is heated for about thirty minutes, the solvent is distilled offin vacuo, 20 ml of ice-water and 200 ml of ether are added to theresidue and the ethereal phase is worked up as usual. 68 percent oft-butyl a-isocyanocyclopentanoate is obtained having a boiling point of52C at 0.2

EXAMPLE 13 EXAMPLE l4 Ethyl l-isocyano-2-( 2'-methylmercaptoethyl )-4-methylpentanoate:

A suspension of 1.1 g (0.045 mole) of sodium hydride in 20 ml of etheris dripped at 20C into 7.5 g 0.04 mole) of ethyla-isocyano-y-methylmcrcaptobutyrate and 10.0 g (0.042 mole) ofisobutylp-toluenesulfonate in 20 ml of dimethylsulfoxide. The whole is stirredfor another hour at 30C. Conventional working up gives 6.5 g (70percent) of ethyl 1-isocyano-2-(2'-methylmercaptoethyl)-4-methyl-pentanoate having a boiling point of 1 to112C.

EXAMPLE Ethyl 4-isocyanotetrahydropyran-4-carboxylate:

2.2 g (0.09 mole) of sodium hydride in 40 ml ofether is dripped at Cinto 4.52 g (0.04 mole) of ethyl isocyanoacetate and 5.8 g (0.042 mole)of 2,2- dichlorodiethyl ether in a mixture of 40 ml of dimethylsulfoxideand 100 ml of ether. The whole is stirred for another hour at 30C andthen worked up as usual. 1.59 g (20 percent) of ethyl4-isocyanotetrahydropyran-4- carboxylate is obtained having a boilingpoint at 3 mm of 105 to 110C.

EXAMPLE 16 Ethyl a-isocyano-B-phenylisobutyrate:

1.1 g (0.045 mole) of sodium hydride in 20 m1 of ether is dripped at 20Cinto 5.2 g (0.04 mole) of ethyl a-isocyanopropionate and 7.1 g (0.042mole) of benzyl bromide in 20 ml of dimethylsulfoxide and 50 ml ofether. The whole is stirred for 1 hour at 30C and worked up as usual.7.0 g (80 percent) of ethyl aisocyano-B-phenylisobutyrate is obtainedhaving a boiling point of 106 to 108C at 0.2 mm.

We claim:

1. A process for production of a compound of the formula where R denoteshydrogen an alkyl group. an alkoxyalkyl group, an alkylthioalkyl group,a cycloalkyl group or a phenyl group, R denotes alkyl or benzyl and R"denotes the alkylating moiety of an alkylating agent defined infra,which comprises reacting an a-metallized isocyanocarboxylic acid esterof the formula:

COOR

where R and R are as defined above, and M denotes the radical oflithium, sodium, potassium. magnesium, calcium or thallium with analkylating agent selected from the group consisting of an alkylmonohalide, an ally] monohalide. an alkyl sulfate. an alkyl ester of anaromatic sulfonic acid, an alkyl sultone, an alkyl phosphoric ester, abenzyl halide, and ethylene oxide to form a compound of the firstformula given above.

2. A process for production of a compound of the formula l to wherein Rand R denote the alkylating moiety of an alkylating agent defined infra,which comprises reacting an a-metallized isocyanocarboxylic acid esterof the formula wherein R denotes alkyl or benzyl and M denotes theradical of lithium, sodium, potassium, magnesium. calcium or thalliumwith 2 mols of an alkylating agent selected from the group consisting ofan alkyl monohalide, an allyl monohalide, an alkyl sulfate. an alkylester of an aromatic sulfonic acid, an alkyl sultone, an alkylphosphoric ester, 21 benzyl halide, and ethylene oxide to form acompound of the first formula given above.

3. A process for production of a compound of the formula where R denoteshydrogen an alkyl group. an alkoxyalkyl group, an alkylthioalkyl group,a cycloalkyl group or a phenyl group, R denotes alkyl or benzyl and Rdenotes an alkylene group, which comprises reacting an a-metallizedisocyanocarboxylic acid ester of the formula:

where R and R denote the groups defined above with an alkyl dihalidehaving R as its alkyl group.

4. A process as claimed in claim 1 wherein the a-metallizedisocyanocarboxylic ester is formed by bringing together a metallizingagent of the metal M and a compound of the formula wherein R has themeaning given above, and the reaction with the alkylating agent iscarried out in the same reaction mixture.

6. A process as claimed in claim 3 wherein the a-metallizedisocyanocarboxylic ester is formed by bringing together a metallizingagent of the metal M and a compound of the formula wherein R and R havethe meanings given above, and the reaction with the alkylating agent iscarried out in the same reaction mixture.

7. A process as claimed in claim 1 carried out with the molar ratio ofisocyanocarboxylic ester to alkylating agent about 1:1.

8. A process as claimed in claim 2 carried out with the molar ratio ofisocyanocarboxylic ester to alkylating agent about 1:2 at -40C to +C.

9. A process as claimed in claim 3 carried out with the molar ratio ofisocyanocarboxylic ester to alkyl dihalide about 2:1.

10. A process as claimed in claim 1 wherein R denotes alkyl having oneto four carbon atoms.

II. A process as claimed in claim 3 wherein R denotes alkyl having oneto four carbon atoms.

12. A process as claimed in claim 2 wherein M in said formula of saidester is first replaced by the radical R by alkylation with one of saidalkylating agents and the hydrogen atom on the metallized carbon isreplaced by the radical R by further alkylation with one of saidalkylating agents via the intermediary radical M.

13. A process as claimed in claim 1 wherein R denotes alkyl with one tofour carbon atoms, phenyl, cyclohexyl, alkoxyalkyl, alkylthioalkyl, andR denotes alkyl of one to four carbon atoms or benzyl.

14. A process as claimed in claim 3 wherein R denotes alkyl with one tofour carbon atoms, phenyl, cyclohexyl, alkoxyalkyl, alkylthioalkyl, andR denotes alkyl of one to four carbon atoms or benzyl.

15. A process as claimed in claim 2 wherein R denotes alkyl of one tofour carbon atoms or benzyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,818,065 nma June 18. 1974 Inventor-(s) Ulrich schoellkopf et a1 It iscertified that 'errorappears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 4, line 43, "Rhu 5" should read --'R Column 8, line 55, inv theformula, "COO', should .read --CO0R Signed and sealed this 7th dayof Jannary 1 975.

(SEAL) Attest: v

McCOY M. GIBSON JR. 0. MARSHALL DANN I Attesting Officer s Commissionerof Patents FORM PO-IOSO (10-69) USCOMM-DC 60876 -P69 v a u.s.sovnmalyl'r PRINTING orrlc: nu 0-866-834.

2. A process for production of a compound of the formula
 3. A processfor production of a compound of the formula
 4. A process as claimed inclaim 1 wherein the Alpha -metallized isocyanocarboxylic ester is formedby bringing together a metallizing agent of the metal M and a compoundof the formula
 5. A process as claimed in claim 2 wherein the Alpha-metallized isocyanocarboxylic ester is formed by bringing together ametallizing agent of the metal M and a compound of the formula
 6. Aprocess as claimed in claim 3 wherein the Alpha -metallizedisocyanocarboxylic ester is formed by bringing together a metallizingagent of the metal M and a compound of the formula
 7. A process asclaimed in claim 1 carried out with the molar ratio ofisocyanocarboxylic ester to alkylating agent about 1:1.
 8. A process asclaimed in claim 2 carried out with the molar ratio ofisocyanocarboxylic ester to alkylating agent about 1:2 at -40*C to+70*C.
 9. A process as claimed in claim 3 carried out with the molarratio of isocyanocarboxylic ester to alkyl dihalide about 2:1.
 10. Aprocess as claimed in claim 1 wherein R1 denotes alkyl having one tofour carbon atoms.
 11. A process as claimed in claim 3 wherein R1denotes alkyl having one to four carbon atoms.
 12. A process as claimedin claim 2 wherein M in said formula of said ester is first replaced bythe radical R4 by alkylation with one of said alkylating agents and thehydrogen atom on the metallized carbon is replaced by the radical R5 byfurther alkylation with one of said alkylating agents via theintermediary radical M.
 13. A process as claimed in claim 1 wherein R1denotes alkyl with one to four carbon atoms, phenyl, cyclohexyl,alkoxyalkyl, alkylthioalkyl, and R2 denotes alkyl of one to four carbonatoms or benzyl.
 14. A process as claimed in claim 3 wherein R1 denotesalkyl with one to four carbon atoms, phenyl, cyclohexyl, alkoxyalkyl,alkylthioalkyl, and R2 denotes alkyl of one to four carbon atoms orbenzyl.
 15. A process as claimed in claim 2 wherein R2 denotes alkyl ofone to four carbon atoms or benzyl.